Lysyl oxidase-like 4 involvement in retinoic acid epithelial wound healing.

Aurélie Comptour,Corinne Belville,Marion Rouzaire,Nicolas Bonnin,Loïc Blanchon,Frédéric Chiambaretta,Vincent Sapin,Estelle Daniel

doi:10.1038/srep32688

Abstract

Vitamin A and its active forms (retinoic acids/RAs) are known to have pro-healing properties, but their mechanisms of action are still poorly understood. This work aimed to identify the cellular and molecular processes by which atRA (all-trans RA) improves wound healing, using an in vivo model of mouse corneal alkali burns and an in vitro cellular human corneal epithelial injury model. Regulation by atRA has been studied on most of the cellular events that occur in wound healing. We investigated the direct influence of atRA on a specific target gene known to be involved in the extracellular matrix (ECM) dynamics, one of the pathways contributing to epithelial repair. Our results demonstrate that atRA promotes corneal epithelial wound healing by acting preferentially on migration. The induction of lysyl oxidase-like 4 (LOXL4) expression by atRA in the corneal epithelium environment was established as essential in the mechanism of atRA-dependent wound healing. Our study describes for the first time a direct link between a retinoic-induced gene and protein, LOXL4, and its general clinical pro-healing properties in ECM dynamics.

Highlights

Epithelial wound healing is a multistep combination of molecular and cellular events that have been extensively studied using epithelial models from skin, lung or cornea
Recent studies describe one component of the plasminogen activator system, tissue type plasminogen activator[30], which must be precisely controlled for ideal wound healing of rat cornea[31]
In vivo study models of wound healing showed that treatment of mouse corneal alkali burns with atRA (1 μM) for 7 days improved ulcer resorption, as seen by fluorescein staining (Fig. 1a)

Summary

Introduction

Epithelial wound healing is a multistep combination of molecular and cellular events that have been extensively studied using epithelial models from skin, lung or cornea. Recent studies describe one component of the plasminogen activator system, tissue type plasminogen activator (tPA) (retinoid-regulated gene involved in ECM dynamics)[30], which must be precisely controlled for ideal wound healing of rat cornea[31]. We characterize and demonstrate for the first time a cellular link between the pro-healing properties of vitamin A and a directly induced gene: LOXL4 These results, obtained for cornea wound healing treatment, open the way to a fully documented understanding of the positive effects of the vitamin A pathway, in the ocular sphere, but more generally in the clinical management of epithelial wound treatment

Objectives

Methods

Results

Conclusion